Model of Neuromuscular Junction May Help Evaluate MG Treatments

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Scientists described a new cellular model of the neuromuscular junction that could be useful for diagnosing myasthenia gravis (MG) or developing new treatments for the condition.

“New approaches for the treatment of neurodegenerative diseases are sorely needed, as decades of research have resulted in limited therapeutic advances. We hope that our models of the human neuromuscular junction can be used in the near future to aid drug discovery and new treatments for some of these diseases,” Olaia F. Vila, PhD, the study’s first author and now a scientist at Amgen, said in a press release.

The study, “Bioengineered optogenetic model of human neuromuscular junction,” was published in the journal Biomaterials.

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The neuromuscular junction, or NMJ, is the region where neurons (nerve cells) come into contact with muscle cells. When a person decides to move, electrical signals travel down from the brain and out through neurons to the NMJ. These electrical signals prompt neurons to release chemical messengers, which ultimately tell the muscles to contract.

In MG, the body’s immune system erroneously attacks components of the NMJ, interfering with nerve-muscle communication and ultimately causing patients to experience fatigue and muscle weakness. This immune attack is driven by self-reactive antibodies that target and attack proteins involved in nerve-muscle communication.

To understand the NMJ, both under healthy conditions and in the context of a disease like MG, it is necessary to have models that are well suited to laboratory studies and also capture the complex biology of these systems.

“Traditionally, studies of the neuromuscular junction rely on small animal models, but the human [NMJ] has key differences, ultimately limiting the utility of animal studies,” said David Rampulla, PhD. Rampulla, who was not directly involved in the study, is director of the division of Discovery Science and Technology at the National Institute of Biomedical Imaging and Bioengineering (NIBIB), which helped to fund this research.

“Here, the study authors have developed a method to evaluate the neuromuscular junction using human 3D tissue models, which enables a more accurate representation of human disease,” Rampulla said.

Put simply, the researchers’ model involves taking human muscle and nerve cells — isolated from a patient’s biopsy or derived from stem cells — and then growing them in a specialized culture dish that keeps the two cell types mostly separate, but allows them to come into contact in a specific way that mimics the 3D architecture of the NMJ in the human body.

To study NMJ activity, researchers employed a technique called optogenetics. Basically, they engineered neurons in the model so that these cells would activate (i.e., send signals across the NMJ to muscle cells) in response to blue light.

Scientists could then shine blue light on nerve cells and record videos of muscle cells contracting in response to signals from neurons. These recordings were then analyzed with computers to measure NMJ activity objectively.

“Such a robust and reproducible methodology allows for repeated measurements of NMJ function and quantification of changes over time or in response to various inputs,” the scientists wrote.

To demonstrate the model’s utility for studying MG, researchers exposed cells making up the model to serum from MG patients. Serum is the noncellular part of blood; of particular relevance, serum from MG patients contains high levels of MG-driving antibodies.

Results showed that treatment with MG serum markedly reduced muscle cell activity, suggesting that these antibodies blocked nerve-muscle communication in this model, just as they do in people with MG.

“Our platform demonstrates that we can quantify the function of both healthy and diseased models of the human neuromuscular junction in an unbiased, reproducible manner,” said Gordana Vunjak-Novakovic, PhD, the study’s senior author from Columbia University.

“Beyond studying the healthy neuromuscular junction, our method can also be adapted for patient-specific models, to either diagnose disease, or eventually to evaluate new treatment modalities for hard-to-treat neuromuscular conditions,” Vunjak-Novakovic added.

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